Exemplary viral pathogens for humans include Herpes simplex viruses 1 and 2 (HSV-1 and HSV-2), which are common human pathogens that are transmitted from person to person by physical contact between infected and uninfected tissues. Characteristically, these viruses vigorously replicate at the portal of entry into the body. Concurrently they are transported retrograde to neurons of ganglia innervating that site [Roizman et al., Herpes simplex viruses. in: Knipe, D. M., Howley, P. M. (Eds.), Fields Virology, sixth ed. 2013. Lippincott Williams & Wilkins, Philadelphia]. In neurons, the viruses establish a latent infection [Al-Dujaili et al., Future Microbiol, 6: 877-907 (2011); Roizman et al., Annu Rev Microbiol 41: 543-71 (1987)]. In the course of latent infection, the genes expressing the viral proteins are repressed [Perng et al., Interdiscip Perspect Infect Dis 2010: 262415 (2010); Knipe et al., Virology 435: 141-56 (2013)] and only a long non-coding RNA designated as latency associated transcript (LAT) [Farrell et al., Proc Natl Acad Sci USA, 88: 790-4 (1991); Spivack et al., J Virol 65: p. 6800-10 (1991); Mitchell et al., J. Gen. Virol. 71: 125-132 (1990); Held et al, J Neurovirol 17: 518-27 (2011)] and micro RNAs are expressed [Cui et al., J Virol 80: p. 5499-508 (2006); Umbach et al., Nature 454: 780-3 (2008); Munson et al., Arch Virol 157: 1677-88 (2012)]. Periodically in response to physical, hormonal, or emotional stress, the virus replicates and is transported to a site at or near the portal of entry into the body where it can cause a lesion. Virus made in the lesion can be transmitted to a non-infected individual [Perng et al., Interdiscip Perspect Infect Dis 2010: 262415 (2010)].
The fundamental problems associated with HSV infections are multifold. HSV-1 is transmitted primarily by oral contact. While in most individuals the recurrent lesions occur at the mucocutaneous region of the lip or genitals (classical fever blisters), the virus is occasionally transported to the brain where it causes encephalitis or to the eye where it causes herpes keratitis. Encephalitis typically occurs in 1 in 100,000 individuals per year, and can cause severe sequelae, including death [Steiner, Curr Opin Neurol 24: 268-74 (2011)]. Recurrent herpes keratitis is a major cause of blindness in the United States [Farooq et al., Sury Ophthalmol 57: 448-62 (2012)]. The problems associated with HSV-2 genital infections can be overwhelming, particularly if the recurrences are frequent, painful or transmitted to a newborn.
Studies on viral latency published to date indicate that: (1) Viral genes form several groups that are coordinately and sequentially derepressed upon productive infection in cell culture and also at the portal of entry into the body [Roizman et al., Cell Cycle 4: 1019-1021 (2005); Roizman et al., J Neurovirol 17: 512-7 (2011)]. Thus, α genes are derepressed with the involvement of VP16, a protein brought into cells during infection [Proenca et al., J Gen Virol 92: 2575-85 (2011)]. At least one a protein designated ICP0 plays a key role in the derepression of β and at least a large fraction of γ genes [Gu et al., Proc Natl Acad Sci USA 104: 17134-9 (2007)]. Following a single incubation of intact trigeminal ganglia in medium containing anti-nerve growth factor (NGF) antibody, genes representative of all coordinately regulated viral genes are derepressed at once in the absence of prior protein synthesis [Du et al., Proc Natl Acad Sci USA 108: 18820-4 (2011)]. In effect, the mechanism of reactivation does not involve VP16 or ICP0; and (2) one hypothesis that could explain the massive derepression of all viral genes at once is that, in the absence of NGF, the neuron undergoes apoptosis [Du et al., Proc Natl Acad Sci USA 109: 14616-21 (2012)]. Indeed, exposure of trigeminal organ cultures to pro-apoptotic drugs induced activation of viral genes in the presence NGF and EGF. However, unlike the spontaneous reactivation in the absence of NGF, the reactivation of viral genes in the presence of at least one pro-apoptotic drug required concurrent protein synthesis [Zhou et al., Proc Natl Acad Sci USA 110: E498-506 (2013)].
Much of the morbidity of HSV-1 and HSV-2 infections is due to the capacity of these viruses to establish latent infections in neurons and to reactivate. In most instances, the replication of HSV-1 and HSV-2 can be controlled by existing antiviral drugs. Importantly, however, antiviral drugs have no effect on latent virus, reactivation frequency or shedding. Adding to the pressure to eliminate reactivating virus is evidence that individuals with recurrent genital HSV infections are more susceptible to HIV infection than those that are not infected.